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Rethinking Metastasis

Most cancer deaths result from metastasis, the spread of cancer from a tumor to other parts of the body. Researchers have long thought that metastasis comes at a late stage of cancer. A new study suggests that the process may start long before that.

A metastatic cell migrates to other parts of the body. Image by Dr. Raouf Guirgus, NCI.

The traditional model of metastasis is that cancer cells need
to accumulate mutations and become fully malignant before they
break away from a tumor and enter the bloodstream or lymphatic
system (the system that produces, stores, and carries the cells
that fight infections). The cells spread to other parts of the
body, where they then grow into metastatic tumors.

Some recent results have raised doubts about this sequence,
and a team of researchers at Memorial Sloan-Kettering Cancer
Center led by Dr. Harold Varmus set out to test the idea. Their
work was supported by grants from NIH's National Cancer Institute
(NCI), the Martell Foundation and the U.S. Department of Defense.

For their experiments, the team used transgenic mice that they
had previously created. The mice express oncogenes—genes
that promote the uncontrolled growth of cancer cells—in
mammary epithelial cells only when fed a chemical switch, doxycycline.
Without doxycycline, the mice don't express the transgenic oncogenes
and have normal mammary glands. Within 3 to 4 weeks after doxycycline
exposure, they develop tumors.

The researchers injected mammary cells from these mice into
the tail veins of other mice that were being fed a diet with
doxycycline. This ensured that the injected cells could transform
only in the bloodstream or tissues of the recipient mouse.

In the September 26, 2008, issue of Science, the researchers
reported that all 4 recipient mice developed lung tumors within
6 weeks after injection of the cells. Control mice that didn't
receive doxycycline didn't develop any tumors. The researchers
then confirmed their results with a similar mouse model. These
elegant experiments show that oncogenes can cause mouse mammary
cells to become tumors within the lung.

To see if the transgenic mammary cells could survive in the
bloodstream and lung without oncogene expression, the researchers
injected the cells into mice that were never exposed to doxycycline.
The oncogenes were tagged to track their expression, but no signal
was detected in the lungs of recipient mice during 4 months of
monitoring. When the mice were given doxycycline 1.5, 8 or 17
weeks after injection of the cells, the cells put out a detectable
signal within 2 weeks. This experiment shows that normal mammary
cells are capable of traveling to and surviving in the lungs.

This study suggests that metastases might arise from normal
cells that travel to other parts of the body early in the cancer
process and then become malignant only when their oncogenes are
activated. This possibility could account for dormancy and late
relapse in human breast cancer. Researchers, however, don't know
if premalignant cells can enter the circulation to become sources
of later metastatic tumors. The authors argue that their experiments
show the idea needs to be further explored.